Glioblastoma (GBM) represents the most common primary malignancy of the central nervous system in adults, and remains a largely incurable disease. The elucidation of disease subtypes based on mutational profiling, gene expression and DNA methylation has so far failed to translate into improved clinical outcomes. However, new knowledge emerging from the subtyping effort in the IDH-wildtype setting may provide directions for future precision therapies. Here, we review recent learnings in the field, and further consider how tumour microenvironment (TME) differences across subtypes may reveal novel contexts of vulnerability. We discuss recent treatment approaches and ongoing trials in the IDH-wildtype GBM setting, and propose an integrated discovery stratagem incorporating multi-omics, single cell technologies and computational approaches.